Intermediates for making HIV-protease inhibitors and methods for making HIV-protease inhibitors

ABSTRACT

HIV protease inhibitors inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. These compounds can be prepared by the novel methods of the present invention using the novel inventive compounds and intermediates.

RELATED APPLICATION DATA

[0001] This application claims priority benefits under 35 U.S.C. § 119based on U.S. Provisional Patent Appln. Ser. No. 60/025,517, filed Sep.5, 1996. This provisional application is entirely incorporated herein byreference. Additionally, this application relates to the following U.S.patent applications: U.S. patent appln. No. Filing Date 08/133,543October 7, 1993 08/133,696 October 7, 1993 08/190,764 February 2, 199408/481,833 June 7, 1995 08/708,411 September 5, 1996

[0002] Each of these U.S. patent applications also is entirelyincorporated herein by reference.

INTRODUCTION

[0003] Treatment of HIV-infected individuals is one of the most pressingbiomedical problems of recent times. A promising new therapy has emergedas an important method for preventing or inhibiting the rapidproliferation of the virus in human tissue. HIV-protease inhibitorsblock a key enzymatic pathway in the virus resulting in substantiallydecreased viral loads, which slows the steady decay of the immune systemand its resulting deleterious effects on human health. The HIV-proteaseinhibitor nelfinavir mesylate of formula 7

[0004] has been shown to be an effective treatment for HIV-infectedindividuals. Nelfinavir mesylate is disclosed in U.S. Pat. No.5,484,926, issued Jan. 16, 1996. This patent is entirely incorporated byreference into this patent application.

[0005] The present inventors have discovered useful intermediatecompounds that can be used in several reaction schemes to makenelfinavir mesylate. The present inventors also have discovered newmethods for making nelfinavir mesylate from the free base nelfinavir offormula 4:

[0006] The nelfinavir free base also is disclosed in U.S. Pat. No.5,484,926.

SUMMARY OF THE INVENTION

[0007] It is an object of this invention to provide compounds andintermediates useful for making HIV-protease inhibitors and methods ofmaking HIV-protease inhibitors. Such inhibitors are useful for treatingHIV-infected individuals.

[0008] In a first aspect, the invention relates to compounds of formula3:

[0009] wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl;heteroaryl; or a group of formula 8

[0010] wherein R₂ is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0011] or further wherein R₁ is a group of formula 9

[0012] wherein each R₃ is independently an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;

[0013] or further wherein R₁ is a group of formula 10

[0014] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group; and

[0015] X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen;pseudohalogen; OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bondedthrough the heteroatom; or N-hydroxyheterocyclic bonded through theoxygen, with the proviso that when R₁ is —CH₃, X cannot be —OCH₃ or —OH,and when R₁ is CH₃C(O)—, X cannot be —OH;

[0016] or a pharmaceutically acceptable salt or solvate thereof.

[0017] In various preferred embodiments of the invention, R₁ is —C(O)CH₃and/or X is a halogen, preferably, Cl.

[0018] In another aspect, the invention relates to compounds of formula2:

[0019] wherein R₁ is a C₂ to C₈ alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, or a group offormula 8

[0020] wherein R₂ is a C₂ to C₈ alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0021] or further wherein R₁ is a group of formula 9

[0022] wherein each R₃ independently is an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;

[0023] or further wherein R₁ is a group of formula 10

[0024] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group;

[0025] or a pharmaceutically acceptable salt or solvate thereof.

[0026] This invention further relates to methods for making thecompounds of formulae 2 and 3. In a method for making a compound offormula 2:

[0027] a compound according to formula 1, shown below,

[0028] is reacted under suitable and sufficient conditions to add an R₁protecting group and form a compound of formula 2. In this instance, R₁is a C₂ to C₈ alkyl group; a cycloalkyl group; a heteroaryl group; or agroup of formula 8

[0029] wherein R₂ is a C₂ alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0030] or R₁ is a group of formula 9

[0031] wherein each R₃ is independently an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;

[0032] or R₁ is a group of formula 10

[0033] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group.

[0034] This invention includes a method of making a compound accordingto formula 3

[0035] This method includes adding, under suitable and sufficientconditions, a suitable protecting group R₁ and a leaving group X to acompound of formula 1

[0036] In this instance, R₁ is alkyl; cycloalkyl; heterocycloalkyl;aryl; heteroaryl; or a group of formula 8

[0037] wherein R₂ is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0038] or R₁ is a group of formula 9

[0039] wherein R₃ is independently an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group;

[0040] or further wherein R₁ is a group of formula 10

[0041] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group; and

[0042] X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen;pseudohalogen; OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bondedthrough the heteroatom; or N-hydroxyheterocyclic bonded through theoxygen, with the proviso that when R₁ is —CH₃, X cannot be —OCH₃ or —OH,and when R₁ is CH₃C(O)—, X cannot be —OH. As noted above, in certainembodiments, R₁ is —C(O)CH₃ and/or X is a halogen, preferably, Cl.

[0043] A compound according to formula 3, as defined above, also can bemade from a compound of formula 2. The reaction proceeds by adding asuitable leaving group X to the compound of formula 2. In this instance,formula 2 is as defined below:

[0044] wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl;heteroaryl; or a group of formula 8

[0045] wherein R₂ is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0046] or further wherein R₁ is a group of formula 9

[0047] wherein each R₃ is independently an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;

[0048] or further wherein R₁ is a group of formula 10

[0049] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group. Additionally, in this instance, X is defined as OH;OR₇, wherein R₇ is alkyl or aryl; halogen; pseudohalogen; OSO₂R₈,wherein R₈ is alkyl or aryl; heteroaryl bonded through the heteroatom;or N-hydroxyheterocyclic bonded through the oxygen. In this method, whenR₁ is —CH₃, X cannot be —OCH₃ or —OH, and when R₁ is CH₃C(O)—, X cannotbe —OH.

[0050] This invention further relates to methods for making HIV-proteaseinhibitors. One HIV-protease inhibitor produced by a method according tothis invention is a compound of formula 4, illustrated below:

[0051] In this method, a compound of formula 3

[0052] wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl;heteroaryl; or a group of formula 8

[0053] wherein R₂ is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0054] or further wherein R₁ is a group of formula 9

[0055] wherein each R₃ independently is an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;

[0056] or further wherein R₁ is a group of formula 10

[0057] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group; and

[0058] X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen;pseudohalogen; OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bondedthrough the heteroatom; or N-hydroxyheterocyclic bonded through theoxygen, is reacted under suitable and sufficient conditions to form thecompound of formula 4. Again, for one preferred embodiment of thisprocess, the variable R₁ represents —C(O)CH₃ and/or the variable Xrepresents Cl.

[0059] The compound according to formula 4, identified above, also canbe prepared by deprotecting a compound of formula 5

[0060] and reacting with it, under sufficient conditions, a compound offormula 3. In this instance, the compound according to formula 3 is

[0061] wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl;heteroaryl; or a group of formula 8

[0062] wherein R₂ is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0063] or further wherein R₁ is a group of formula 9

[0064] wherein each R₃ independently is an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;

[0065] or further wherein R₁ is a group of formula 10

[0066] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group; and

[0067] X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen;pseudohalogen; OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bondedthrough the heteroatom; or N-hydroxyheterocyclic bonded through theoxygen.

[0068] In another embodiment of this invention, a compound of formula 4,as identified above, can be prepared by combining a compound of formula3:

[0069] wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl;heteroaryl; or a group of formula 8

[0070] wherein R₂ is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0071] or further wherein R₁ is a group of formula 9

[0072] wherein each R₃ independently is an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;

[0073] or further wherein R₁ is a group of formula 10

[0074] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group; and

[0075] X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen;pseudohalogen; OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bondedthrough the heteroatom; or N-hydroxyheterocyclic bonded through theoxygen, with a compound of formula 6

[0076] under conditions sufficient and suitable to obtain the compoundof formula 4.

[0077] This invention further relates to methods of making a compound offormula 7. In one embodiment, the compound of formula 7

[0078] is produced by converting a compound of formula 4

[0079] under sufficient and suitable conditions to the compound offormula 7. In this method, the conversion of the compound of formula 4to the compound of formula 7 takes place by:

[0080] (a) contacting the compound of formula 4 with an organic solvent;

[0081] (b) contacting the compound of formula 4 with methanesulfonicacid under conditions sufficient to form a compound of formula 7; and

[0082] (c) spray drying the compound of formula 7. In a more specificembodiment of this method, the organic solvent is ethanol.

[0083] In another method for making a compound of formula 7 from acompound of formula 4, the following procedure is followed:

[0084] (a) the compound of formula 4, a suitable solvent, andmethanesulfonic acid are combined to form the compound of formula 7, thecompound of formula 7 being dissolved in solution;

[0085] (b) a first antisolvent is added to the solution containing thecompound of formula 7;

[0086] (c) the compound of formula 7 and the first antisolvent areagitated together to form a product having a solid phase and a liquidphase; and

[0087] (d) the product is filtered and washed with a second antisolvent,the second antisolvent being the same as or different from the firstantisolvent, to obtain a solid final product according to formula 7.After the solid final product is washed, it can be dried by anyappropriate method or means. Tetrahydrofuran can be used as the solvent,and diethylether can be used as at least one antisolvent, preferably atleast the first antisolvent.

[0088] This invention also relates to a method of making a compoundaccording to formula 4 (as defined above) from a compound according toformula 2. In this method, a compound according to formula 2 is reactedunder sufficient and suitable conditions to form the compound of formula4. In this instance, the compound of formula 2 is defined as follows:

[0089] wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl;heteroaryl; a group of formula 8

[0090] wherein R₂ is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0091] or further wherein R₁ is a group of formula 9

[0092] wherein each R₃ independently is an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;

[0093] or further wherein R₁ is a group of formula 10

[0094] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group.

[0095] Yet another embodiment of this invention relates to a method ofmaking a compound of formula 7, defined above. In this method, acompound according to formula 5

[0096] is deprotected. Then, the deprotected compound of formula 5 isreacted, under sufficient and suitable conditions, with a compound offormula 3. Formula 3, in this instance, is defined as follows:

[0097] wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl;heteroaryl; or a group of formula 8

[0098] wherein R₂ is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group;

[0099] or further wherein R₁ is a group of formula 9

[0100] wherein each R₃ independently is an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;

[0101] or further wherein R₁ is a group of formula 10

[0102] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group; and

[0103] X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen;pseudohalogen; OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bondedthrough the heteroatom; or N-hydroxyheterocyclic bonded through theoxygen. The reaction of compounds 3 and 5 produces a compound of formula4, described above. The compound according to formula 4 is thenconverted to the compound of formula 7, for example, by one of themethods described above.

DETAILED DESCRIPTION OF THE INVENTION

[0104] This invention relates to compounds and intermediates useful formaking HIV-protease inhibitors, methods of making the compounds andintermediates, and methods of making HIV-protease inhibitors.

[0105] As mentioned above, one aspect of this invention relates tocompounds that are useful (e.g., as starting materials or intermediates)for making HIV-protease inhibitors. One such group of compounds areidentified in this application by formula 3, shown below:

[0106] wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl;heteroaryl; a group of formula 8

[0107] wherein R₂ is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, O—R₆ (wherein R₆ is an alkyl group, an aralkylgroup, or an aryl group); a group of formula 9

[0108] wherein each R₃ independently is an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;or a group of formula 10

[0109] wherein R₄and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group; and

[0110] X is OH; OR₇ (wherein R₇ is alkyl or aryl); halogen;pseudohalogen, including azide, cyanide, isocyanate and isothiocyanate;OSO₂R₈ (wherein R₈ is alkyl or aryl); heteroaryl bonded through theheteroatom; or N-hydroxyheterocyclic, including hydroxysuccinimide orhydroxybenzotriazole ester, bonded through the oxygen, with the provisothat when R₁ is —CH₃, X cannot be —OCH₃ or —OH, and when R₁ is CH₃C(O)—,X cannot be —OH; and to pharmaceutically acceptable salts and solvatesthereof. Preferably X is a halogen, particularly, Cl.

[0111] The present invention also is directed to novel compounds offormula 2

[0112] wherein R₁ is a C₂ to C₈ alkyl group; a cycloalkyl group; aheterocycloalkyl group; an aryl group; a heteroaryl group; a group offormula 8

[0113] wherein R₂ is a C₂ to C₈ alkyl group, a cycloalkyl group, aheterocycloalkyl group, O—R₆ (wherein R₆ is an alkyl group, an aralkylgroup, or an aryl group); a group of formula 9

[0114] wherein each R₃ independently is an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;or a group of formula 10

[0115] wherein R₄ and each R₅ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group; and to pharmaceutically acceptable salts and solvatesthereof.

[0116] When R₁ is a group of formula 8 where R₂ is alkyl, R₁ can be, forexample, acetate, propanoate, butanoate, pivaloate, or any related alkylester or mixed carbonate with a group such as benzyl. Other examples ofR₁ groups where R₁ is a group of formula 8 include esters of aromaticand heteroaromatic acids, such as benzoate, substituted benzoate, 1- or2-naphthoate or substituted 1- or 2-naphthoate, or a substituted 5- or6-membered heteroaromatic ester. Examples of R₁ groups where R₁ is analkyl include methyl, substituted methyl, ethyl, propyl, and butyl.Examples of R₁ when R₁ is a silyl ether of formula 9 includetrimethylsilyl, t-butyidimethylsilyl, triisopropylsilyl, triphenylsilyl,and silyl ethers where the alkyl groups R₃ are some combination ofsimple alkyl and aryl groups. Examples of R₁ where R₁ is part of anacetal or ketal of formula 10 include acetonide, cyclohexylidene ketal,benzylidene acetal, 2-methoxyethoxyethyl acetal, and related acetals andketals where R₄ and R₅ are alkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl. In certain preferred compounds of formulae 2 and 3, and inpharmaceutically acceptable salts and solvates thereof, R₁ is —C(O)CH₃;alternatively expressed, R₂ in a group of formula 8 is CH₃.

[0117] The present invention is further directed to various methods ofmaking compounds of formulae 2, 3, 4 (nelfinavir free base), and 7(nelfinavir mesylate), as described above. Other methods of preparingnelfinavir free base using compounds of formulae 2 and 3 are describedin U.S. patent Appln. Ser. No. 08/708,607, filed Sep. 5, 1996, whichapplication also is entirely incorporated herein by reference. Othermethods of using compounds of Formulae 2 and 3 are disclosed in JP95-248183 and JP 95-248184, each of which is entirely incorporatedherein by reference.

[0118] As used in the present application, the following definitionsapply:

[0119] The term “alkyl” as used herein refers to substituted orunsubstituted, straight or branched chain groups, preferably, having oneto eight, more preferably having one to six, and most preferably havingfrom one to four carbon atoms. The term “C₁-C₆ alkyl” represents astraight or branched alkyl chain having from one to six carbon atoms.Exemplary C₁-C₆ alkyl groups include methyl, ethyl, n-propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl,isohexyl, and the like, The term “C₁- C₆ alkyl” includes within itsdefinition the term “C₁-C₄ alkyl.”

[0120] The term “cycloalkyl” represents a substituted or unsubstituted,saturated or partially saturated, mono- or poly-carbocyclic ring,preferably having 5-14 ring carbon atoms. Exemplary cycloalkyls includemonocyclic rings having from 3-7, preferably 3-6, carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike. Exemplary cycloalkyls are C₅-C₇ cycloalkyls, which are saturatedhydrocarbon ring structures containing from five to seven carbon atoms.

[0121] The term “aryl” as used herein refers to an aromatic, monovalentmonocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18carbon ring atoms, which may be unsubstituted or substituted, and towhich may be fused one or more cycloalkyl groups, heterocycloalkylgroups, or heteroaryl groups, which themselves may be unsubstituted orsubstituted by one or more suitable substituents. Illustrative examplesof aryl groups include, but are not limited to, phenyl, naphthyl,anthryl, phenanthryl, fluoren-2-yl, indan-5-yl, and the like.

[0122] The term “halogen” represents chlorine, fluorine, bromine, oriodine. The term “halo” represents chloro, fluoro, bromo, or iodo.

[0123] The term “carbocycle” represents a substituted or unsubstitutedaromatic or a saturated or a partially saturated 5-14 memberedmonocyclic or polycyclic ring, which is substituted or unsubstituted,such as a 5- to 7-membered monocyclic or 7- to 10-membered bicyclicring, wherein all the ring members are carbon atoms.

[0124] A “heterocycloalkyl group” is intended to mean a non-aromatic,monovalent monocyclic, bicyclic, or tricyclic radical, which issaturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2, 3, 4, or5 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein theradical is unsubstituted or substituted, and to which may be fused oneor more cycloalkyl groups, aryl groups, or heteroaryl groups, whichthemselves may be unsubstituted or substituted. Illustrative examples ofheterocycloalkyl groups include, but are not limited to, azetidinyl,pyrrolidyl, piperidyl, piperazinyl, morpholinyl,tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl,tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl,azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl,oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.

[0125] A “heteroaryl group” is intended to mean an aromatic monovalentmonocyclic, bicyclic, ortricyclic radical containing 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5heteroatoms selected from nitrogen, oxygen, and sulfur, which may beunsubstituted or substituted, and to which may be fused one or morecycloalkyl groups, heterocycloalkyl groups, or aryl groups, whichthemselves may be unsubstituted or substituted. Illustrative examples ofheteroaryl groups include, but are not limited to, thienyl, pyrrolyl,imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl,thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl,xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl,purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl,tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyi,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, andphenoxazinyl.

[0126] The term “acyl” represents L₆C(O)L₄, wherein L₆ is a single bond,—O, or —N, and further wherein L₄ is preferably alkyl, amino, hydroxyl,alkoxyl, or hydrogen. The alkyl, amino, and alkoxyl groups optionallycan be substituted. An exemplary acyl is a C₁-C₄ alkoxycarbonyl, whichis a straight or branched alkoxyl chain having from one to four carbonatoms attached to a carbonyl moiety. Exemplary C₁-C₄ alkoxycarbonylgroups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, and the like. Another exemplary acylis a carboxy wherein L₆ is a single bond and L₄ is alkoxyl, hydrogen, orhydroxyl. A further exemplary acyl is N—(C₁-C₄)alkylcarbamoyl (L₆ is asingle bond and L₄ is an amino), which is a straight or branched alkylchain having from one to four carbon atoms attached to the nitrogen atomof a carbamoyl moiety. Exemplary N-(C₁-C₄)alkylcarbamoyl groups includeN-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, and N-t-butylcarbamoyl, and thelike. Yet another exemplary acyl is N,N-di(C₁-C₄)alkylcarbamoyl, whichhas two straight or branched alkyl chains, each having from one to fourcarbon atoms attached to the nitrogen atom of a carbamoyl moiety.Exemplary N,N-di(C₁-C₄)alkylcarbamoyl groups includeN,N-dimethylcarbamoyl, N,N-ethylmethylcarbamoyl,N,N-methylpropylcarbamoyl, N,N-ethylisopropylcarbamoyl,N,N-butylmethylcarbamoyl, N,N-sec-butylethylcarbamoyl, and the like.

[0127] Suitable protecting groups are recognizable to those skilled inthe art. Examples of suitable protecting groups can be found in T. Green& P. Wuts, Protective Groups in Organic Synthesis (2d ed. 1991), whichis incorporated herein by reference.

[0128] The term “aralkyl” as used herein refers to any substituted orunsubstituted group that is sp³ hybridized at the point of attachmentthat also possesses an aromatic ring or rings with that group.

[0129] The term “pseudohalogen” as used herein refers to azides,cyanides, isocyanates, and isothiocyanates.

[0130] The term “N-hydroxyheterocyclic” as used herein refers tosubstituted and unsubstituted groups having an oxygen atom at the pointof attachment that is also bonded to the nitrogen of a nitrogenheterocyclic ring or ring system. Examples of such groups include:

[0131] The term “alkyl ester” as used herein refers to ester groupswhere the group attached to the esterifying oxygen is an alkyl group.

[0132] The term “mixed carbonate” as used herein refers to compoundscontaining the functional group

[0133] where R_(a) and R_(b) independently are alkyl, aryl, or aralkylgroups.

[0134] The term “ester of an aromatic or heteroaromatic acid” as usedherein refers to carboxylic acids wherein the carboxyl group is attacheddirectly to a substituted or unsubstituted aromatic or heteroaromaticring, such as benzoic acid or 2-furoic acid.

[0135] The term “DABCO” as used herein refers to the reagent1,4-diazabicyclo[2.2.2]octane.

[0136] The term “DBN” as used herein refers to the reagent1,5-diazabicyclo[4.3.0]non-5-ene.

[0137] The term “DBU” as used herein refers to the reagent1,8-diazabicyclo[5.4.0]undec-7-ene.

[0138] The term “silyl ether” as used herein refers to the group:

[0139] wherein R_(c), R_(d), and R_(e) independently are alkyl, aryl oraralkyl groups.

[0140] The term “perfluoralkanesulfonate” as used herein refers toalkane sulfonate esters wherein one or more of the hydrogens arereplaced by fluorines.

[0141] The term “vinyl alkyl ether” as used herein refers to ethergroups where an alkyl group and a substituted or unsubstitutedolefin-containing group are bonded to the ethereal oxygen, and theolefin-containing group is bonded to the ethereal oxygen at one of thedoubly-bonded carbons.

[0142] The term “arylsufonic acid” as used herein refers to groups offormula:

[0143] wherein Ar is a substituted or unsubstituted aromatic ring.

[0144] The term “leaving group” as used herein refers to any group thatdeparts from a molecule in a substitution reaction by breakage of abond. Examples of leaving groups include, but are not limited to,halides, arenesulfonates, alkylsulfonates, and triflates.

[0145] The term “arenesulfonate” as used herein refers to anysubstituted or unsubstituted group that is an ester of an arylsulfonicacid.

[0146] The term “alkyl or aryl carbodiimides” as used herein refers toany reagent of formula R_(f)—N═C═N—R_(g), wherein R_(f) and R_(g)independently are aryl, alkyl, or aralkyl.

[0147] The term “DMF” as used herein refers to the solventN,N-dimethylformamide.

[0148] The term “NMP” as used herein refers to the solventN-methyl-2-pyrolidinone.

[0149] The term “THF” as used herein refers to the solventtetrahydrofuran.

[0150] The term “alkyl thiolates” as used herein refers to substitutedor unsubstituted compounds that are metal salts of alkanethiols.

[0151] The term “trialkylsilyl halides” as used herein refers tocompounds having a silicon that holds 3 alkyl groups that may be thesame or different.

[0152] The term “hydrogenolysis” as used herein refers to a reaction inwhich a single bond is broken and hydrogens become bonded to the atomsthat were formerly bonded.

[0153] Examples of substituents for alkyl and aryl include mercapto,thioether, nitro (NO₂), amino, aryloxyl, halogen, hydroxyl, alkoxyl, andacyl, as well as aryl, cycloalkyl, and saturated and partially saturatedheterocycles. Examples of substituents for cycloalkyl include thoselisted above for alkyl and aryl, as well as aryl and alkyl.

[0154] Exemplary substituted aryls include a phenyl or naphthyl ringsubstituted with one or more substituents, preferably one to threesubstituents, independently selected from halo; hydroxy;morpholino(C₁-C₄)alkoxy carbonyl; pyridyl (C₁-C₄)alkoxycarbonyl; halo(C₁-C₄)alkyl; C₁-C₄ alkyl; C₁-C₄ alkoxy; carboxy; C₁-C₄ alkoxycarbonyl;carbamoyl; N—(C₁-C₄)alkylcarbamoyl; amino; C₁-C₄alkylamino;di(C₁-C₄)alkylamino; or a group of the formula —(CH₂)_(a)—R⁷ where a is1, 2, 3, or 4, and R⁷ is hydroxy, C₁-C₄ alkoxy, carboxy, C₁-C₄alkoxycarbonyl, amino, carbamoyl, C₁-C₄ alkylamino, ordi(C₁-C₄)alkylamino.

[0155] Another substituted alkyl is halo(C₁-C₄)alkyl, which represents astraight or branched alkyl chain having from one to four carbon atomswith 1-3 halogen atoms attached to it. Exemplary halo(C₁-C₄)alkyl groupsinclude chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl,2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl, andthe like.

[0156] Another substituted alkyl is hydroxy(C₁-C₄)alkyl, whichrepresents a straight or branched alkyl chain having from one to fourcarbon atoms with a hydroxy group attached to it. Exemplaryhydroxy(C₁-C₄)alkyl groups include hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl, and the like.

[0157] Yet another substituted alkyl is C₁-C₄ alkylthio(C₁-C₄)alkyl,which is a straight or branched C₁-C₄ alkyl group with a C₁-C₄ alkylthiogroup attached to it. Exemplary C₁-C₄ alkylthio(C₁-C₄)alkyl groupsinclude methylthiomethyl, ethyithiomethyl, propylthiopropyl,sec-butylthiomethyl, and the like.

[0158] Yet another exemplary substituted alkyl is heterocycle(C₁-C₄)alkyl, which is a straight or branched alkyl chain having from one tofour carbon atoms with a hetero-cycle attached to it. Exemplaryheterocycle(C₁-C₄)alkyls include pyrrolylmethyl, quino-linylmethyl,1-indolylethyl, 2-furylethyl, 3-thien-2-ylpropyl, 1-imidazolylisopropyl,4-thiazolylbutyl, and the like.

[0159] Yet another substituted alkyl is aryl(C₁-C₄)alkyl, which is astraight or branched alkyl chain having from one to four carbon atomswith an aryl group attached to it. Exemplary aryi(C₁-C₄)alkyl groupsinclude phenylmethyl, 2-phenylethyl, 3-naphthyl-propyl,1-naphthylisopropyl, 4-phenylbutyl, and the like.

[0160] The heterocycloalkyls and heteroaryls can, for example, besubstituted with 1, 2, or 3 substituents independently selected fromhalo; halo(C₁-C₄)alkyl; C₁-C₄ alkyl; C₁-C₄ alkoxy; carboxy; C₁-C₄alkoxycarbonyl; carbamoyl; N-(C₁-C₄)alkylcarbamoyl; amino;C₁-C₄alkylamino; di(C₁-C₄)alkylamino; or a group having the structure—(CH₂)_(a)-R⁷ where a is 1, 2, 3, or 4, and R⁷ is hydroxy, C₁-C₄ alkoxy,carboxy, C₁-C₄ alkoxycarbonyl, amino, carbamoyl, C₁-C₄alkylamino, ordi(C₁-C₄)alkylamino.

[0161] Examples of substituted heterocycloalkyls include, but are notlimited to, 3-N-t-butyl carboxamide decahydroisoquinolinyl and6-N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl. Examples ofsubstituted heteroaryls include, but are not limited to,3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl,4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl,3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl,4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethyinaphthyl,2-methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl,2-t-butoxycarbonyl-1,2,3,4-isoquinolin-7-yl, and the like.

[0162] A “pharmaceutically acceptable solvate” is intended to mean asolvate that retains the biological effectiveness and properties of thebiologically active components of compounds of formulae 2 and 3.

[0163] Examples of pharmaceutically acceptable solvates include, but arenot limited to, compounds prepared using water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

[0164] In the case of solid formulations, it is understood that theinventive compounds can exist in different forms, such as stable andmetastable crystalline forms and isotropic and amorphous forms, all ofwhich are intended to be within the scope of the present invention.

[0165] A “pharmaceutically acceptable salt” is intended to mean thosesalts that retain the biological effectiveness and properties of thefree acids and bases and that are not biologically or otherwiseundesirable.

[0166] Examples of pharmaceutically acceptable salts include, but arenot limited to, sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates,tartrates, methanesulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0167] If the inventive compound is a base, the desired salt can beprepared by any suitable method known in the art, including treatment ofthe free base with an inorganic acid, such as hydrochloric acid;hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and thelike, or with an organic acid, such as acetic acid; maleic acid;succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid;oxalic acid; glycolic acid; salicylic acid; pyranosidyl acids such asglucuronic acid and galacturonic acid; alpha-hydroxy acids such ascitric acid and tartaric acid; amino acids such as aspartic acid andglutamic acid; aromatic acids such as benzoic acid and cinnamic acid;sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid; orthe like.

[0168] If the inventive compound is an acid, the desired salt can beprepared by any suitable method known in the art, including treatment ofthe free acid with an inorganic or organic base, such as an amine(primary, secondary, or tertiary), an alkali metal or alkaline earthmetal hydroxide, or the like. Illustrative examples of suitable saltsinclude organic salts derived from amino acids such as glycine andarginine; ammonia; primary, secondary, and tertiary amines; and cyclicamines such as piperidine, morpholine, and piperazine, and inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum, and lithium.

[0169] All inventive compounds that contain at least one chiral centercan exist as single stereoisomers, racemates, and/or mixtures ofenantiomers and/or diastereomers. All such single stereoisomers,racemates, and mixtures thereof are intended to be within the scope ofthe present invention. Preferably, the compounds of the presentinvention are used in a form that contains at least 90% of a singleisomer (80% enantiomeric or diastereomeric excess), more preferably atleast 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95%e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).Compounds identified herein as single stereoisomers are meant todescribe compounds used in a form that contains at least 90% of a singleisomer.

[0170] The inventive compounds can be prepared by the novel methods ofthe present invention, which are described in detail below.Additionally, these compounds can be used to prepare nelfinavir freebase and nelfinavir mesylate according to the inventive methodsdescribed below.

[0171] A reaction scheme for the conversion of 3-hydroxy-2-methylbenzoicacid derivatives to neifinavir free base is as follows:

[0172] The acid 1 is commercially available from Lancaster Labs andSugai Chemical Industries, Ltd. in Japan. The acid 1 also can beobtained according to the procedure described in U.S. Pat. No.5,484,926, for the Preparation of 9C.

[0173] When R₁ is an acyl group or an ester of an aromatic orheteroaromatic acid, R₁ can be installed onto 3-hydroxy-2-methylbenzoicacid (Step 1) using the corresponding acyl halides or anhydrides intypical organic solvents for these types of reactions, such ashalogenated solvents, ethers, and hydrocarbons accompanied by a base.Such bases typically are inorganic bases, such as metal hydroxides,bicarbonates, and carbonates, or organic bases, such as amines liketriethylamine, diethylamine, diethyl isopropylamine, DABCO, or relateddi- or trialkylamines, as well as amidine bases like DBU and DBN. Thesereactions typically are run anywhere from below room temperature toapproximately 100° C. Alternatively, the esterification can be catalyzedby acids such as sulfuric acid when used in conjunction with anhydrides.

[0174] When R₁ is an ether group, R₁ can be installed using conditionsthat utilize the corresponding R₁ group bonded to a leaving group, whichis subsequently displaced. These reactions generally are performed inmost common organic solvents such as THF, diethyl ether, dioxane, methylt-butyl ether, or other ethers; esters such as ethyl, methyl, andisopropyl acetate; halogenated solvents such as halogenated methanes andethanes, chlorobenzene, and other halogenated benzenes; nitrites suchacetonitrile and propionitrile; lower alcohols such as ethanol,isopropanol, t-butanol, and related alcohols; and polar organic solventssuch as dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrolidinone,and related amide-containing solvents. A base usually accompanies such aprocess. The bases typically are inorganic, such as metal hydroxides,bicarbonates, and carbonates, or organic, such as amines liketriethylamine, diethylamine, diethyl isopropylamine, DABCO, or relateddi- or trialkylamines, as well as amidine bases like DBU and DBN. Thesereactions typically are run anywhere from below room temperature toapproximately 100° C.

[0175] When R₁ is a silyl ether, it can be installed using thecorresponding silyl halides or perfluoralkanesulfonates in most commonorganic solvents such as THF, diethyl ether, dioxane, methyl t-butylether, or other ethers; esters such as ethyl, methyl, and isopropylacetate; halogenated solvents such as halogenated methanes and ethanes,chlorobenzene, and other halogenated benzenes; nitriles suchacetonitrile and propionitrile; and polar organic solvents such asdimethylformamide, N-methyl-2-pyrolidinone, and related amide-containingsolvents. A base usually accompanies such a process. The bases typicallyare inorganic bases, such as metal hydroxides, bicarbonates, andcarbonates, or organic bases, such as amines like triethylamine,diethylamine, diethyl isopropylamine, DABCO, or related di- ortrialkylamines, as well as amidine bases like DBU and DBN.

[0176] When R₁ is part of an acetal or ketal group, R₁ can be installedby alkylation with the corresponding α-haloether in a manner similar toother alkyl halides as described above. Alternatively, acid-promotedaddition of 3-hydroxy-2-methylbenzoic acid to the corresponding vinylalkyl ether can be used. These reactions are promoted by both organicacids (such as p-toluenesulfonic and related alkyl and arylsulfonicacids, trifluoroacetic acid and related organic carboxylic acids with apK of less than 2) and inorganic acids (such as sulfuric, hydrochloric,phosphoric, and nitric acids).

[0177] The group X is installed in Step 2 by reaction of the carboxylicacid derivative 2. The acyl halides of formula 3 can be prepared usinginorganic halogenating agents such as thionyl chloride or bromide,phosphorus trichloride or -bromide, phosphorus pentachloride or bromide,or organic agents such as oxalyl chloride or trichlorisocyanuric acid.This process can be catalyzed by DMF or a related alkyl amide.

[0178] Esters of formula 3 can be prepared in a variety of ways startingfrom the acid chloride (compounds of formula 3) by combination with thedesired alcohol in the presence of an organic or inorganic base statedpreviously. Alternatively, the ester can be produced by acid-promotedesterification in the presence of the desired alcohol. The sulfonatesusually are made by reaction of the carboxylic acid derivatives(compounds of formula 2) with alkyl or arylsulfonyl chlorides in thepresence of an organic amine base such as triethylamine in a non-polarsolvent at temperatures below 0° C. The pseudohalogen derivativesgenerally are made from the acid halides (compounds of formula 3) byreaction with inorganic pseudohalide in the presence of a base. Theheteroaryl derivatives (compounds of formula 2) also are made from theacid halides of formula 3 utilizing the specific heteroaryl compound inthe presence of an amine base in a non-polar solvent. TheN-hydroxyheterocyclic derivatives can be made from the acid halides offormula 3 as above and can also be generated using alkyl or arylcarbodiimides and an amine base as condensing agents.

[0179] The coupling of compound 3 to amine 6 (Step 3) can be carried outin a variety of ways, depending on the identity of X. When a free acidis used (X═OH), the coupling can be performed using carbodiimide basedmethods utilizing any of the common reagents of this class includingdicyclohexylcarbodiimide or related dialkylcarbodiimides, EDC (salts of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) or related water solublereagents along with an organic amine base in polar organic solvents suchas dioxane, DMF, NMP, and acetonitrile in the presence of anN-hydroxyheterocyclic including hydroxysuccinimide orN-hydroxybenzotriazole ester. When X is a halogen or pseudohalogen, thecoupling can be performed in most common organic solvents such as THF;diethyl ether, dioxane, methyl t-butyl ether, or other ethers; acetone,cyclohexanone, methyl isobutylketone and other ketones; esters such asethyl, methyl, and isopropyl acetate; halogenated solvents such ashalogenated methanes and ethanes; chlorobenzene and other halogenatedbenzenes; nitrites such acetonitrile and propionitrile; lower alcoholssuch as ethanol, isopropanol, t-butanol, and related alcohols; and polarorganic solvents such as dimethylformamide, dimethylsulfoxide,N-methyl-2-pyrolidinone, and related amide-containing solvents. A basefrequently is used and can be any of a number of inorganic bases (suchas metal hydroxides, bicarbonates, and carbonates) or organic bases(such as amines like triethylamine, diethylamine, diethylisopropylamine, DABCO, or related di- or trialkylamines, as well asamidine bases like DBU and DBN).

[0180] Protecting group removal is accomplished using any of thestandard methods for deprotecting a particular class of protectinggroup. Esters and carbonates usually are removed with aqueous oralcoholic solutions of inorganic bases, such as metal hydroxides,carbonates, and bicarbonates, at ambient temperatures up to 100° C.Ethers are deprotected using boron-based Lewis acidic compounds such asBBr₃ and BCl₃, alkyl thiolates, or trialkylsilyl halides. Either etheror carbonate protecting groups that contain benzyl groups bonded toheteroatoms can be removed by hydrogenolysis with a palladium orplatinum catalyst. Acetal-based protecting groups can be removed underaqueous or alcoholic acidic conditions, promoted by Lewis acids such astransition metal halides or halides of the Group 3 metals, or by proticorganic acids (such as p-toluenesulfonic and related alkyl andarylsulfonic acids, trifluoroacetic acid and related organic carboxylicacids with a pK of less than 2) and inorganic acids (such as sulfuric,hydrochloric, phosphoric, and nitric acids). Silylether protecting groupremoval can be accomplished by aqueous or alcoholic acid or base or byfluoride ion promoted desilylation by use of inorganic fluoride sourcessuch as potassium or cesium fluoride or by tetralkylammonium fluoridesalts.

[0181] Nelfinavir mesylate can be prepared from3-acetoxy-2-methylbenzoyl chloride (acid chloride). The acid chloridecan be prepared from the corresponding 3-hydroxy-2-methylbenzoic acid inthe following two step procedure:

[0182] In the production of the acid chloride, the acid 1 is convertedto the acetoxy acid (a compound of formula 2), which is treated withthionyl chloride to give 3-acetoxy-2-methylbenzoyl chloride in goodyield.

[0183] The acid chloride then can be coupled to the amine 6 underclassical conditions resulting in the production of nelfinavir free baseas follows:

[0184] The acid chloride is treated with the amine 6 in the presence oftriethylamine in THF at ambient temperature for 30 minutes followed byan aqueous basic hydrolysis of the acetate group to give nelfinavir freebase. The free base can be converted to nelfinavir mesylate by methodsdescribed in more detail below.

[0185] Preparation of Nelfinavir Free Base from3-Acetoxy-2-Methylbenzoic Chloride

[0186] Summary of the Process

[0187] To obtain 3-acetoxy-2-methylbenzoyl chloride,3-hydroxy-2-methylbenzoic acid was slurried in acetic acid with aceticanhydride and catalytic sulfuric acid. Acetylation of the hydroxy groupwas complete within two hours at ambient temperature. After completereaction, the resulting slurry was poured into water, and the productwas isolated by filtration. The wet cake was reslurried in water,isolated by filtration, and dried under vacuum. Product was obtained in80-90% yield with an apparent purity of 89-92% by HPLC. Crude, dry3-acetoxy-2-methylbenzoic acid was dissolved in four volumes of ethylacetate with refluxing. The resulting solution was cooled to <70° C.,and five volumes of hexanes were added. The mixture was returned toreflux and then cooled to <10° C. for 1 hour. The slurry was filtered,rinsing the reactor with filtrate. The product was dried under vacuum.Recrystallization improved the HPLC UV apparent purity from 89-92%to >98%. The single largest impurity dropped from 4-5% to ˜0.5%. Theproduct was 3-acetoxy-2-methylbenzoic acid.

[0188] 3-Acetoxy-2-methylbenzoic acid was slurried in methyl-t-butylether (MTBE) and treated with 1.2 equivalents of thionyl chloride andcatalytic dimethylformamide. After three hours at ambient temperatures,the reaction was complete, giving a brown solution. Solvent (MTBE) wasremoved by vacuum distillation. Residual thionyl chloride was removed byaddition of toluene followed by vacuum distillation. The resulting3-acetoxy-2-methylbenzoyl chloride was isolated either directly as anoil or by crystallization from two volumes of heptane at <10° C. Productwas obtained in >100% yield when isolated as an oil and 82-85% yieldwhen crystallized from heptane.

[0189] To obtain compound 6 for the coupling, a compound of formula 5(made as described below) was refluxed in a mixture of ethanol andaqueous NaOH to cleave the CBZ protecting group forming a compound offormula 6. Water and HCl were added to dissolve the Na₂CO₃ andneutralize excess NaOH, giving a biphasic mixture. The mixture wascooled, and the lower aqueous layer was removed. Triethylamine was addedfollowed by a solution of 3-acetoxy-2-methylbenzoyl chloride intetrahydrofuran to give an acetate of the compound of formula 4. AqueousNaOH was added, and the mixture was heated to reflux to give a compoundof formula 4. The mixture was concentrated at atmospheric pressure toremove tetrahydrofuran, triethylamine, and most of the ethanol. Themixture was added to a heated solution of water and glacial acetic acidto precipitate the product. The pH was adjusted with additional acid,and the solids were filtered off while hot. The wet cake was rinsed withhot water and dried to give crude nelfinavir free base.

[0190] This method is described in more detail below.

[0191] Preparation of 3-Acetoxy-2-methylbenzoic acid

[0192] Procedure

[0193] Materials 3-hydroxy-2-methylben- FW 152.15 3500 g 1.0 equiv zoicacid acetic acid 8750 mL sulfuric acid 70 mL acetic anhydride FW 102.1 d1.082 2390 mL 1.1 equiv purified water 28000 mL

[0194] Acetic acid (8750 mL), 3-hydroxy-2-methylbenzoic acid (3500 g),and sulfuric acid (70 mL) were charged into a 22 liter reactor. Thereactor contents were stirred to give a homogeneous mixture. The mixtureexothermed to 36° C. Acetic anhydride (2390 mL) was added to the mixturein the 22 L reactor. An exotherm warmed the reactor contents from 36 to44° C. The reaction mixture was stirred at ambient temperature for twohours (reactor contents allowed to cool slowly). The reaction was testedfor complete conversion of the starting material by TLC. The reactionmixture was generally a tan slurry at the completion of the reaction.

[0195] Purified water (17500 mL) was added to a 50 L extractor, and thereaction mixture from the 22 L reactor was added to this water. The 22 Lreactor was rinsed into the 50 L extractor with purified water (3500mL). The reaction mixture was vacuum filtered, washing the reactor andfilter cake with purified water (3500 mL). The wet filter cake wastransferred to a 50 L extractor, and purified water (14000 mL) wasadded, with stirring, to obtain a homogeneous slurry. The reslurriedmixture was vacuum filtered, and the reactor and filter cake were rinsedwith purified water (3500 mL). The filter cake was pulled as dry aspossible and then transferred to drying pans. The product was dried in avacuum oven at 60-80° C. and ≧28 mm Hg for 12-72 hours. Theoreticalyield: 4466 g. Actual weight produced: 3910 g (87.6%). HPLC assay: 89.4%or 87.7%.

[0196] Purification was achieved as follows. The crude3-acetoxy-2-methylbenzoic acid (3910 g from above) and ethyl acetate(16.0 L) were charged to a 50 L reactor. The reactor contents wereheated to reflux (77°0 C.) until all solids went into solution. Thereactor contents were cooled to <70° C. Hexanes (19.5 L) were added tothe reactor. The reactor contents were again heated to reflux (69° C.),and then the mixture was cooled to <10° C. for 1 hour. The cooled slurryfrom this step was vacuum filtered, and the reactor was rinsed with coldmother liquors. The filter cake was pulled as dry as possible and thentransferred to drying pans. The product was dried in a vacuum oven at60-70° C. and ≧28 mm Hg for 12-72 hours. Theoretical yield: 3910 g.Actual weight produced: 3128 g (80%). This procedure improves the HPLCUV apparent purity from 89-92% to >98%. The single largest impuritydrops from 4-6% to <1%. The isolated product is a tan solid. ¹H NMR δ8.0(d, 1H), 7.3 (overlapping m, 2H), 2.5 (s, 3H), 2.3 (s, 3H).

[0197] Preparation of 3-Acetoxy-2-methylbenzoyl Chloride

[0198] Procedure Materials MW d wt equiv. 3-acetoxy-2-methylbenzoic194.19 3000 g 1.0 acid methyl-t-butyl ether 12000 ml thionyl chloride118.97 1.638 1350 ml 1.2 dimethylformamide 73.09 0.944 60 ml 0.05toluene 7500 ml heptane 7500 ml

[0199] A 22 L reactor was purged with nitrogen and charged withrecrystallized 3-acetoxy-2-methylbenzoic acid (3000 g), MTBE (12000 ml),and dimethylformamide (60 ml). The reactor contents were stirred to givea homogeneous mixture. Thionyl chloride (1350 ml) was added to thereactor. This reaction mixture was stirred at ambient temperature for 19hours. (Generally no more than 3 hours are required for completereaction, but the mixture can be held longer for convenience). Thereaction solution was transferred to a Büchi rotovap, and the reactorwas rinsed with toluene (1500 ml). The solution was concentrated as faras possible, maintaining the bath temperature at 40-50° C. Toluene (6000ml) was added to this concentrated solution. The toluene was distilledby rotovap to drive off excess thionyl chloride. The concentrate wastransferred back to the 22 L reactor, and the Büchi flask was rinsedwith heptane (6000 ml). The heptane mixture was cooled to <5° C. undernitrogen. After holding the crystallization mixture at <5° C. for >30minutes, the mixture was filtered, and the filter cake was washed withchilled heptane (1500 ml, <5° C.). The filter cake was dried in a vacuumoven at 15-20° C. and ≧28 mm Hg for 24 hours, giving a tan, granularsolid. Theoretical yield: 3285 g. Actual weight produced: 2704 g(82.3%). HPLC assay 97.51%; ¹H NMR δ 8.1 (d, 1H), 7.4 (overlapping m,2H), 2.4 (s, 6H).

[0200] Conversion of 3-Acetoxy-2-methylbenzoyl Chloride and Compound 6to Nelfinavir Free Base

[0201] Step A: Conversion of Compound 5 to Compound 6.

[0202] A 22 liter 3-neck round bottom flask (“RBF”), fitted with acondenser, temperature probe, and mechanical stirrer, was charged with acompound of formula 5 (1 kg, 97.7%, 1.72 mol, 1.00 eq) (which can beprepared as described below), ethanol (5 l, 95%), NaOH (280 ml, 50%,5.33 mol, 3.1 eq), and water (2 l, Dl). The mixture was stirred andheated to reflux (80-82° C.). All solids dissolved at 50° C. to give aclear yellow solution. The mixture became hazy with Na₂CO₃ precipitationas the reaction proceeded (Vol=8280 ml). The deprotection was monitoredby HPLC. Analysis at 210 minutes showed complete consumption of thecompound of formula 5, 0.95% oxazolidinone, 36% benzyl alcohol, and62.5% of a compound of formula 6. Analysis at 300 minutes showed 0.34%oxazolidinone, 36% benzyl alcohol and 62.6% of compound of formula 6.Water (1260 ml) was added to the mixture to dissolve all solids, and themixture was cooled to 67° C. (Vol=9540 ml). HCl (344 ml, 6 N, 2.06 mol,1.2 eq.) was then added to the mixture. The mixture was agitated 10minutes and then allowed to settle for 20 minutes to give two layers(Vol=9884 ml). The lower aqueous Na₂CO₃ layer was removed at 60° C. Thevolume of the aqueous cut was 365 ml, pH=14. The pH of the clear yellowupper layer was 10-10.5. The upper layer was used directly in the nextstep.

[0203] Step B: Conversion of Compound 6 to an Acetate of Compound 4.

Chemicals source assay Kg L d mw mol equiv Compound 6/EtOH 1040-090(0.746) 433.65 (1 72) 1 00 triethylamine Fisher 0.26 0.36 0.726 101.192.58 1 50 tetrahydrofuran Fisher 0.40 0.45 0.889 72.113-acetoxy-2-methylbenzoyl AC1322 98.9% 0 39 212.63 1 81 1 05 chlorideReference: 1040-092

[0204] The solution from Step A was cooled to 25° C., triethylamine (360ml, 2.58 mol, 1.50 eq) was added to the solution, and the mixture wascooled to 7° C. (pH=11.5-12.0). The mixture became hazy at 23° C.(Vol=9879 ml). This mixture was charged to a mixture of3-acetoxy-2-methylbenzoyl chloride (388.5 g, 98.8%, 1.81 mol, 1.05 eq)and tetrahydrofuran (440 ml) over 5 minutes. THF (10 ml) was used tocomplete the transfer. A 7.4° C. exotherm was observed. The mixture atthe end of the addition was milky white. (Vol=10,717 ml). HPLC analysisafter 30 minutes showed <0.2% of a compound of formula 6, 77% of theacetate of the compound of formula 4, 18.2% benzylalcohol, and no esterpresent. The milky mixture was used directly in the next step.

[0205] Step C: Saponification of Compound 4.

Chemicals source assay Kg L d mw mol equiv Acetate of Compound 4/PA1040-092 (1 05) 609 83 (1 72) 1 00 NaOH Fisher 50% 0.55 0.36 1.515 40 006 88 4 00 Water Dl 15.0 15 1.000 18 02 HOAc. glacial Fisher 17.4 N 0.250.23 1 049 60.05 4 07 2.37 Ethanol. (5% methanol) McCormack 95% 0.04 005 0.785 46.07

[0206] NaOH (50%, 364 ml, 6.88 mol, 4.0 eq) was added to the mixturefrom Step B. The milky mixture became clear, then hazy, light brown. Themixture was agitated at 20° C. for 35 minutes. HPLC showed 15.9%benzylalcohol, 78.6% of compound 4, and no acetate (Vol=11,081 ml). Themixture was heated to reflux and partially concentrated by atmosphericdistillation until the head temperature reached 82° C. The distillatevolume was 4275 ml. The pH of the mixture was 14. The pot volume wasmeasured (Vol=6000 ml).

[0207] Water (5 L) and HOAc (100 mL) were charged to a 12 L 3-neck roundbottom flask fitted with a temperature probe and mechanical stirrer. Thesolution was heated to 54° C. (pH=2-2.5) (Vol=5100 ml). One half of thecompound 4 mixture produced above (3 L) was added to this warm aqueousacetic acid solution to precipitate fine white solids. The pH was thenadjusted to 7-7.5 with HOAc (19 ml), and the temperature was 53° C.(Vol=8119 ml). The solids were filtered off at 53° C. using isolatedvacuum. The filtration was quick and easy. The reactor and wet cake wererinsed with warm (35° C.) water (2.5 L), and the filtrates werecombined. The wet cake was pulled dry for 15-20 minutes.

[0208] Water (5 L) and HOAc (100 mL) were charged again to the 12 L 3-neck round bottom flask. The solution was heated to 41° C. (Vol=5100ml). The remaining half of the compound 4 reaction mixture (3 L) wasadded to the new warm aqueous acetic acid solution to precipitate finewhite solids. The pH was then adjusted to 7-7.5 with HOAc (15 ml). Thetemperature was 44° C. (Vol=8115 ml). The solids were filtered off at53° C. using isolated vacuum. The filtration was quick and easy. Thereactor and wet cake were rinsed with warm (35° C.) water (2.5 L), andthe filtrates were combined. The wet cake was pulled dry for 15-20minutes.

[0209] The two wet cakes (3587 g) were dried under vacuum at 60° C. for90 hours to give a dry wt of 1075.38 g crude Compound 4. Theoreticalyield is 977 g.

[0210] Step D: Purification of Compound 4 Chemicals source assay wt ml dmw mmol equiv Crude Compound 4 895-131 91.82%  290 g 567.79 469 1 00Acetone Fisher 4038 g 5105 0.791 58.08 Water DI 1070 g 1070 1.000 18.02Celite Aldrich  29 g Darco G-60 activated Fisher  44 g 12.01 carbon

[0211] A 12 liter 3-neck RBF, fitted with a condenser, temperatureprobe, and mechanical stirrer, was charged with crude compound 4 (290 g,92%, 469 mmol), activated carbon (Darco G-60, 44 g), acetone (4305 ml),and water (870 ml, Dl). The mixture was heated to reflux (60-64° C.) andheld 45 minutes (Vol=5509 ml). The hot slurry was filtered throughcelite (29 g) using isolated vacuum. The reactor and filter cake wererinsed with acetone (200 ml), and the clear, light yellow filtrates werecombined. The mixture was allowed to cool slowly to 25° C. over 2.5hours with stirring to precipitate a fine white solid (Vol=5665 ml). Thewhite slurry was cooled to 0-10° C. and held for 1 hour. The solids werefiltered off using isolated vacuum, and the liquid level was pulledthrough the surface of the wet cake. The reactor and wet cake wererinsed with a cold (0-10° C.) mixture of acetone/water (2:1, 300 ml).The liquid level was pulled through the surface of the wet cake, and thereactor and wet cake were again rinsed with a cold (0-10° C.) mixture ofacetone/water (2:1, 300 ml). The wet cake was pulled as dry as possibleusing isolated vacuum and rubber damming to give a wet weight of 581 g.The product was dried under vacuum at 65° C. for 16 hours to give a dryweight of 221.61 g of compound 4. Theoretical yield was 266.28 g. HPLCand ROI analysis showed 99% and 0.14% respectively. Adjusted yield was82%.

[0212] The present invention also is directed to novel methods ofconverting nelfinavir free base, compound 4, to nelfinavir mesylate,compound 7. These methods are described in more detail below, includingthe method for preparing compound 4 from compound 6 and the method forpreparing compound 5.

[0213] Procedure for Preparation of Compound 5

[0214] One equivalent 2S,3R-N-Cbz-3-amino-1-chlorophenylsulfanylbutan-2-ol (which can be obtainedfrom Kaneka Corporation or prepared as described in U.S. Pat. No.5,484,926) is stirred in a sufficient volume of methanol, ethanol,isopropanol, or other low boiling alcoholic solvent at 20°-45° C.Isopropanol is the preferred solvent. A slight subcess of alkali base,such as sodium hydroxide or potassium hydroxide, as either an aqueoussolution or as a solid, is added to this mixture with stirring. 10Nsodium hydroxide is the preferred base. The mixture is stirred for 30minutes to 24 hours until epoxide formation is complete. When the stirperiod is complete, the pH is adjusted to 6-7 with a proton acid such asHCl, either neat or dissolved in the reaction solvent.

[0215] A slight excess of3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline (which can beprepared as described in U.S. Pat. No. 5,256,783, which patent isentirely incorporated herein by reference) is added as either a drysolid or as a slurry to the reaction, and the mixture is heated to 40°C. to reflux for 12-24 hours or until the reaction is judged to becomplete. Alternatively,3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline can be introducedto the reaction at the same time that the 2S,3R-N-Cbz-3-amino-1-chlorophenylsulfanylbutan-2-ol is charged to reactor.The epoxide formation is allowed to proceed as described. In this case,the reaction is not neutralized to a pH of 6-7, but a fixed amount ofproton acid is added to neutralize excess base remaining. In eithercase, the reaction is partially concentrated in vacuo. The mixture isdiluted with an equal volume of water and heated to reflux.Alternatively, the reaction is fully concentrated, and acetone or otherketonic solvent is added. The mixture can be filtered at this point,then an equal amount of water is added, and the mixture is heated. Theresultant mixture is cooled with stirring. The resultant slurry isfiltered, washed with aqueous solvent, and dried to yield compound 5.

[0216] Procedure for Preparation of Nelfinavir Free Base (Compound 4)

[0217] In addition to the procedure described above, the followingprocedure can be used to convert compound 6 to the nelfinavir free base(compound 4):

[0218] One equivalent of compound 5, an excess of alkali base (such assodium hydroxide or potassium hydroxide), and an alcoholic solvent (suchas methanol, ethanol, or isopropanol) are combined, and the mixture isheated at reflux with stirring. 50% caustic soda is the preferred baseand isopropanol is the preferred solvent. Water can be added tofacilitate solubility of the base. When the reaction is judged complete,the mixture is cooled to 30° to 35° C., and the lower aqueous layer, ifany, can be removed. The mixture is cooled to below 25° C. and an excessamount of organic base (such as diisopropylethyl amine or triethylamine)is added. Triethylamine is the base of choice.

[0219] A solution of excess 3-acetoxy-2-methylbenzoyl chloride inmethanol, ethanol, isopropanol, THF, or other alcohol soluble solventsis slowly added to the cold mixture with stirring. THF is the preferredsolvent.

[0220] An excess of alkali base, such as sodium hydroxide or potassiumhydroxide, is added, and the mixture is heated at 40° C. to reflux withstirring. 50% caustic soda is the preferred base. When the reaction isjudged complete, the mixture is cooled, and the lower aqueous layer isremoved.

[0221] The reaction mixture is partially concentrated in vacuo. Ifdeemed necessary, the mixture can be diluted with an alcohol solvent tofacilitate stirring. Methanol is the preferred solvent. The mixture isadded to aqueous acid to form a slurry. HCl is the preferred acid. ThepH is adjusted to 7-8 with aqueous acid. The slurry is filtered andwashed with water. The wet cake can be reslurried in water. The crudeproduct is dried (partially or completely) or can be taken into the nextstep wet.

[0222] Either the dry or the crude, wet product is dissolved in aqueousacetone at reflux in the presence of activated carbon. The hot mixtureis filtered, water is added, and the entire mixture is cooled withstirring to form a slurry. The slurry is filtered, washed with aqueousacetone, and dried to give nelfinavir free base.

[0223] Other methods for preparing nelfinavir free base are disclosed inU.S. Pat. No. 5,484,926, and copending U.S. patent application ofinventors S. Babu, B. Borer, T. Remarchuk, R. Szendroi, K. Whitten, J.Busse, and K. Albizati, entitled “Methods of Making HIV-ProteaseInhibitors and Intermediates for Making HIV-Protease Inhibitors,” U.S.Patent Appln. Ser. No. 08/708,607, filed on Sep. 5, 1996, whichapplication is incorporated herein by reference.

[0224] Procedure for Spray Drying Nelfinavir Free Base to ObtainNelfinavir Mesylate

[0225] Generally, nelfinavir free base can be converted to nelfinavirmesylate using the following novel spray drying procedure.

[0226] Nelfinavir free base and an organic solvent (such as methanol,ethanol, isopropanol, THF, acetone, or MIBK) are mixed in a suitablevessel, and an equivalent amount of methanesulfonic acid is added.Ethanol is the preferred solvent. The mixture is stirred untilnelfinavir mesylate is formed. The resultant slurry or solution ispumped into the spray dryer where the following settings are controlled:Inlet Temperature: 100-190° C. Outlet Temperature:  60-120° C. AtomizerType: vane, cocurrent flow, or counter current flow Drying Gas Rate:depends on equipment scale

[0227] The inlet and outlet temperatures, feed rate, and atomizer typecan be adjusted to optimize output and particle size distribution. Spraydried nelfinavir mesylate is collected at the spray dryer outletcollection point.

[0228] Specifically, this conversion was performed as described below.

[0229] 19.4 kg±5% Alcohol (USP 190 proof) and 6.00 kg±1% nelfinavir freebase were added to a clean, dry 20-40 L stainless steel container. Themixture was stirred until homogenous, then 1.04 kg±1% methanesulfonicacid, 99%, was added. The mixture was stirred until all solids weredissolved. A 0.2 μ filter cartridge was connected to the pump inlet, andthe alcohol solution was pumped through the filter into the spray dryerset with the following initial settings: Inlet Temperature: 160° C.Outlet Temperature: 90° C. Wheel Type: 50 mm vane wheel Wheel Speed:27000 rpm Drying Gas Rate: 75 kgs./hour

[0230] The inlet and outlet temperatures, feed rate, and wheel speed canbe adjusted to optimize output and particle size distribution. Thespecific spray dryer used was a Niro Atomizer Portable Spray Dryer, typeHT (equipped for inert gas) connected to an active carbon filter forremoval of organic solvent residues. After the bulk of the solution hadbeen spray dried, the mixing tank was rinsed into the spray dryer with1.0 kg±5% Alcohol, USP, 190 proof. The spray dried nelfinavir mesylatewas collected in 80-100% theory yield.

[0231] Procedure for Precipitation of Nelfinavir Free Base to ObtainNelfinavir Mesylate

[0232] Alternatively, nelfinavir free base can be converted tonelfinavir mesylate using the following novel precipitation procedure.

[0233] Nelfinavir free base is slurried or dissolved in a suitablesolvent (such as THF, methanol, or ethanol). THF is the preferredsolvent. A molar equivalent amount of methanesulfonic acid is added, andthe mixture is stirred until all solids dissolve. The solution is addedto several volumes of an antisolvent (such as methyl t-butyl ether,diethyl ether, hexanes, or heptanes) that is rapidly stirring. Diethylether is the preferred antisolvent. After stirring, the mixture isfiltered and washed with antisolvent. The solid is dried in a vacuumoven to yield nelfinavir mesylate.

[0234] Specifically, this conversion was performed as described below.

[0235] Nelfinavir free base (10.2 kg, 18.0 mol) and 24 L oftetrahydrofuran were added to a 100 L reactor. Methanesulfonic acid (1.8kg, 18.48 mol) also was added to the reactor. The reactor was stirreduntil all solids dissolved, and then the solution was filtered into a100 gallon polypropylene tank containing 306 L methyl t-butyl ether ordiethyl ether that was rapidly stirring. After stirring for 2 hours, the100 gallon tank contents were filtered, washed with 17 L of methylt-butyl ether or diethyl ether, and pulled as dry as possible. The solidwas transferred to a rotocone drier and dried in a vacuum oven at 60-65°C. (at least 26 in. Hg or higher vacuum) for 12-72 hours or until themethyl t-butyl ether or diethyl ether content of the dried solid wasbelow 1%. If necessary, the drier contents could be milled in a Fitzmillgrinder to accelerate drying. Typical yields of nelfinavir mesylaterange from 9 to 11 kg. (76% -92% theory).

[0236] In this application, Applicants have described certain theoriesand reaction mechanisms in an effort to explain how and why thisinvention works in the manner in which it works. These theories andmechanisms are set forth for informational purposes only. Applicants arenot to be bound by any particular chemical, physical, or mechanicaltheory of operation.

[0237] While the invention has been described in terms of variouspreferred embodiments using specific examples, those skilled in the artwill recognize that various changes and modifications can be madewithout departing from the spirit and scope of the invention, as definedin the appended claims.

We claim:
 1. A compound of formula 3:

wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; ora group of formula 8

wherein R₁ is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, or O—R₆, wherein R₆ is an alkyl group, an aralkyl group, or anaryl group; or further wherein R₁ is a group of formula 9

wherein each R₃ is independently an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₅ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;and X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen; pseudohalogen;OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bonded through theheteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with theproviso that when R₁ is —CH₃, X cannot be —OCH₃ or —OH, and when R₁ isCH₃C(O)—, X cannot be —OH; or a pharmaceutically acceptable salt orsolvate thereof.
 2. A compound according to claim 1, wherein R₁ is—C(O)CH₃.
 3. A compound according to claim 2, wherein X is Cl.
 4. Acompound according to claim 1, wherein X is Cl.
 5. A compound of formula2:

wherein R₁ is a C₂ to C₈ alkyl group; a cycloalkyl group; aheterocycloalkyl group; an aryl group; a heteroaryl group; or a group offormula 8

wherein R₂ is a C₂ to C₈ alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group; or further wherein R₁ is a group offormula 9

wherein each R₃ independently is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₅ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;or a pharmaceutically acceptable salt or solvate thereof.
 6. A method ofmaking a compound of formula 2:

comprising: adding under sufficient conditions a suitable protectinggroup R₁ to a compound of formula 1

wherein R₁ is a C₂ to C₈ alkyl group; a cycloalkyl group; aheterocycloalkyl group; an aryl group; a heteroaryl group; or a group offormula 8

wherein R₂ is a C₂ to C₈ alkyl group, a cycloalkyl group, aheterocycloalkyl group, or O—R₆, wherein R₆ is an alkyl group, anaralkyl group, or an aryl group; or further wherein R₁ is a group offormula 9

wherein each R₃ is independently an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₅ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;to form the compound of formula
 2. 7. A method of making a compound offormula 3

comprising: adding under sufficient conditions a suitable protectinggroup R₁ and a leaving group X to a compound of formula 1

wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; ora group of formula 8

wherein R₂ is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, or O—R₆, wherein R₆ is an alkyl group, an aralkyl group, or anaryl group; or further wherein R₁ is a group of formula 9

wherein each R₃ is independently an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₅ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;and X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen; pseudohalogen;OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bonded through theheteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with theproviso that when R₁ is —CH₃, X cannot be —OCH₃ or —OH, and when R₁ isCH₃C(O)—, X cannot be —OH; to form the compound of formula
 3. 8. Amethod according to claim 7, wherein R₁ is —C(O)CH₃.
 9. A methodaccording to claim 7, wherein X is Cl.
 10. A method according to claim9, wherein R₁ is —C(O)CH₃.
 11. A method of making a compound of formula3

comprising: adding under sufficient conditions a leaving group X to acompound of formula 2

wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; ora group of formula 8

wherein R₂ is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, or O—R₆, wherein R₆ is an alkyl group, an aralkyl group, or anaryl group; or further wherein R₁ is a group of formula 9

wherein each R₃ is independently an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₅ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;and X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen; pseudohalogen;OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bonded through theheteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with theproviso that when R₁ is —CH₃, X cannot be —OCH₃ or —OH, and when R₁ isCH₃C(O)—, X cannot be —OH; to form the compound of formula
 3. 12. Amethod according to claim 11, wherein X is Cl.
 13. A method of making acompound of formula 4

comprising: converting under sufficient conditions a compound of formula3

wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; ora group of formula 8

wherein R₂ is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, or O—R₆, wherein R₆ is an alkyl group, an aralkyl group, or anaryl group; or further wherein R₁ is a group of formula 9

wherein each R₃ independently is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₅ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;and X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen; pseudohalogen;OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bonded through theheteroatom; or N-hydroxyheterocyclic bonded through the oxygen, to thecompound of formula
 4. 14. A method according to claim 13, wherein R₁ is—C(O)CH₃.
 15. A method according to claim 13, wherein X is Cl.
 16. Amethod according to claim 15, wherein R₁ is —C(O)CH₃.
 17. A method ofmaking a compound of formula 4

comprising: deprotecting a compound of formula 5

and adding to the deprotected compound of formula 5, under sufficientconditions, a compound of formula 3:

wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; ora group of formula 8

wherein R₂ is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, or O—R₆, wherein R₆ is an alkyl group, an aralkyl group, or anaryl group; or further wherein R₁ is a group of formula 9

wherein each R₃ independently is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₅ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;and X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen; pseudohalogen;OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bonded through theheteroatom; or N-hydroxyheterocyclic bonded through the oxygen, to formthe compound of formula
 4. 18. A method according to claim 17, whereinR₁ is —C(O)CH₃.
 19. A method according to claim 17, wherein X is Cl. 20.A method according to claim 19, wherein R₁ is —C(O)CH₃.
 21. A method ofmaking a compound of formula 4

comprising: combining under sufficient conditions a compound of formula3:

wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; ora group of formula 8

wherein R₂ is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, or O—R₆, wherein R₆ is an alkyl group, an aralkyl group, or anaryl group; or further wherein R₁ is a group of formula 9

wherein each R₃ independently is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₅ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;and X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen; pseudohalogen;OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bonded through theheteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with acompound of formula 6

to obtain the compound of formula
 4. 22. A method according to claim 21,wherein R₁ is —C(O)CH₃.
 23. A method according to claim 21, wherein X isCl.
 24. A method according to claim 23, wherein R₁ is —C(O)CH₃.
 25. Amethod of making a compound of formula 7

comprising: converting under sufficient conditions a compound of formula4

to the compound of formula 7 by: (a) contacting the compound of formula4 with an organic solvent; (b) contacting the compound of formula 4 withmethanesulfonic acid under conditions sufficient to form a compound offormula 7; and (c) spray drying the compound of formula
 7. 26. A methodaccording to claim 25, wherein the organic solvent is ethanol.
 27. Amethod of making a compound of formula 7

comprising: converting under sufficient conditions a compound of formula4

to the compound of formula 7 by: (a) combining the compound of formula4, a suitable solvent, and methanesulfonic acid to form the compound offormula 7, the compound of formula 7 being dissolved in solution; (b)adding a first antisolvent to the solution containing the compound offormula 7; (c) agitating the compound of formula 7 and the firstantisolvent to form a product having a solid phase and a liquid phase;and (d) filtering and washing the product with a second antisolvent, thesecond antisolvent being the same as or different from the firstantisolvent, to obtain a solid.
 28. A method according to claim 27, themethod additionally comprising: (e) drying the solid.
 29. A methodaccording to claim 27, wherein the suitable solvent is tetrahydrofuran.30. A method according to claim 27, wherein the first antisolvent isdiethyl ether.
 31. A method of making a compound of formula 4

comprising: converting under sufficient conditions a compound of formula2

wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; agroup of formula 8

wherein R₂ is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, or O—R₆, wherein R₆ is an alkyl group, an aralkyl group, or anaryl group; or further wherein R₁ is a group of formula 9

wherein each R₃ independently is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₅ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;to the compound of formula
 4. 32. A method according to claim 31,wherein R₁ is —C(O)CH₃.
 33. A method of making a compound of formula 7

comprising: deprotecting a compound of formula 5

adding to the deprotected compound of formula 5, under sufficientconditions, a compound of formula 3:

wherein R₁ is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; ora group of formula 8

wherein R₂ is an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, or O—R₆, wherein R₆ is an alkyl group, an aralkyl group, or anaryl group; or further wherein R₁ is a group of formula 9

wherein each R₃ independently is an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; or furtherwherein R₁ is a group of formula 10

wherein R₄ and each R₁ independently are an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;and X is OH; OR₇, wherein R₇ is alkyl or aryl; halogen; pseudohalogen;OSO₂R₈, wherein R₈ is alkyl or aryl; heteroaryl bonded through theheteroatom; or N-hydroxyheterocyclic bonded through the oxygen, to forma compound of formula 4:

and converting the compound of formula 4 to the compound of formula 7.